The mechanism of a Chinese herbal formula on cancer pain

描述（由申请人提供）：拟议的关于中草药配方治疗癌症疼痛机制的国际研究是我们正在进行的父母资助的延伸，由NIH资助，P01-AT002605（9/2005 - 8/201010）和R21 AT 004113（2/1/08 - 1/31/10）。老立兴博士，项目负责人，针刺对持续性炎症性疼痛作用机制的P01研究和针刺对癌症相关疼痛作用的C0-I研究。该项目将与中国上海长征医院（CZ）徐玲医生合作进行。疼痛是与癌症相关的最常见和最令人恐惧的症状之一，但尚未得到充分控制。几千年来，中药一直被用来治疗包括疼痛在内的各种疾病。劳博士和他的团队一直在研究癌症引起的疼痛，他的合作者徐凌博士一直在研究中医对癌症相关疾病（包括疼痛）的影响。先前的研究表明，破骨细胞活性与骨癌疼痛有关，并导致血清骨碱性磷酸酶（BAP）和1型胶原羧基末端吡啶啉交联末端肽（ICTP）水平升高。瞬时受体电位通道、香草蛋白亚家族成员1 （TRPV1）、TRPA1和TRPV4也与持续性疼痛有关。我们的初步研究表明，一种草药配方，TLSJ，已经在临床上使用，减轻了骨癌患者和大鼠模型的疼痛。本课题旨在评价TLSJ治疗癌性疼痛的有效性和安全性，并探讨其在雌雄大鼠模型中的作用机制。我们假设外用TLSJ凝胶可以通过抑制破骨细胞活性来抑制癌症疼痛，这可以通过降低血清BAP和ICTA水平以及背根神经节（DRG）中TRP通道的表达来证明。三个目的是：目的1 a)确定TLSJ凝胶对雄性和雌性骨癌疼痛大鼠模型癌性疼痛的影响。自发性疼痛、热痛觉过敏和机械性痛觉过敏/异常性痛将在草药治疗后确定。b)确定TLSJ的安全性。将通过监测动物的行为变化来研究可能的不良反应，并通过生化试验和组织学检查确定配方的毒性。目标2。探讨TLSJ凝胶对癌痛患者破骨活性及BAP、ICTP水平的影响。组织学检查骨破骨活性。采用ELISA法测定血清BAP和ICTP。目的：探讨TLSJ凝胶对TRP通道表达的影响。TRPV1， TRPA1和TRPV4拮抗剂将用于表征TRP参与骨癌疼痛。免疫组织化学染色检测三个通道的DRG表达。实验的成功将为设计临床试验研究中药对持续性癌症疼痛的影响提供初步数据。这将有助于开发有效和安全的替代/补充治疗癌症疼痛。

DESCRIPTION (provided by applicant): the proposed international research study on mechanisims of a Chinese herbal formula on cancer pain is an extension of our ongoing parents grants funded by NIH, P01-AT002605 (9/2005 - 8/201010) and R21 AT 004113 (2/1/08 - 1/31/10). Dr. Lixing Lao, the PI is the project leader of the P01 study on acupuncture's mechanisms of action on persistent inflammatory pain and C0-I of the study on the effect of acupuncture on cancer-related pain. The proposed project will be performed in collaboration with Dr. Ling Xu at Changzheng Hospital (CZ), Shanghai, China. Pain, one of the most common and feared symptoms associated with cancer, is not yet adequately controlled. Chines herbal medicine has been used for thousands of years to treat a variety of ailments, including pain. Dr. Lao and his team have been undertaking investigations on carcionoma-induced pain, and his collaborator, Dr. Ling Xu has been investigating the effect of Traditional Chinese Medicine (TCM) on cancer-related disorders, including pain. Previous studies show that osteoclastic activitiesare involved in bone cancer pain and cause elevated levels of serum bone alkaline phosphatase (BAP) and carboxyterminal pyridlinoline cross-linked telopeptide of type 1 collagen (ICTP). Transient receptor potential channels, vanilloid subfamily member 1 (TRPV1), and TRPA1, and TRPV4 are also involved persistent pain. Our pilot studies showed that an herbal formula, TLSJ, which has been used clinically, alleviated bone cancer pain in patients and in a rat model. The objective of the proposal is to evaluate the efficacy and safety of TLSJ on cancer pain and explore its mechanisms in male and female rat models. We hypothesize that external applications of a TLSJ gel will inhibit cancer pain by suppressing osteoclast activities, evidenced by decrasig levels of serum BAP and ICTA, and TRP channel expression in dorsal root ganglia (DRG). The three aims are: Aim 1 a) To determine the effect of TLSJ Gel on cancer-induced pain in male and female rat models of bone cancer pain. Spontaneious pain, thermal hyperalgesia and mechanical hyperalgesia/allodyna will be determined following herb treatment. b) To determine the safety of TLSJ. Possible adverse effects will be studied by monitoring the animals for behavioral changes, and the toxicity of the formula will be determined by biochemical assay and histological examination. Aim 2. To investigate effects of TLSJ Gel on osteoclasic activity and BAP and ICTP levels during cancer pain. Bone osteeoclastic activity will be hisologically examined. Serum BAP and ICTP will be measured using ELISA. Aim e. To investigate effects of TLSJ Gel on TRP channel expression. TRPV1, TRPA1 and TRPV4 antagonists will be used to characterize TRP involvement in bone cancer pain. DRG expression of the three channels will be examined by immunohistochemical staining. The success of the experiments will provide preliminary data for designing clinical trials to study the effects of Chinese herbs on persistent cancer pain. This will facilitate the development of effective and safe alternative/complementary treatment for cancer pain. PUBLIC HEALTH RELEVANCE: Pain occurs frequently incancerpatients and has not been controlled adequately. Acupuncture has been used for millennia to treat pain. This study will evaluate the effects and mechanisms of an herb formula Tongluo Sanjie (TLSJ) on such pain in rat models. The success of the proposed study will greatly advance the management of cancer pain.